There is increasing interest and research into the roles that genes and brain systems play in influencing psychiatric illnesses, but a major obstacle in identifying these influences is the complex nature of diagnostic categories. A potential solution is to focus on intervening variables, or endophenotypes, that are likely more sensitive to the effects of genetic variation or brain systems than are heterogeneous, non-biologically-based diagnostic categories. Such an endophenotype is impulsivity, the predisposition to respond to stimuli without considering the consequences. Impulsivity ranges from normal to pathological and characterizes many forms of psychopathology. Although there is evidence supporting a neural basis of impulsivity, and evidence supporting the role of dopamine in influencing impulsivity, there have been only limited attempts to combine this information to identify the neurogenetic bases of impulsivity. This project will test the hypothesis that variants of two dopamine system-related genetic polymorphisms (DAT and COMT) influence the neural network underlying behavioral inhibition, a more direct expression of impulsivity. Specifically, healthy adults pre-selected for genotypes of the DAT and COMT polymorphisms will perform a Stop-signal task, which measures behavioral inhibition, while they undergo functional magnetic resonance imaging (fMRI). This task was chosen because it directly addresses the ability to inhibit a response; fMRI was chosen because neural activation is likely more sensitive to the effects of genetic variation than self-report, clinical diagnosis, or even behavioral performance alone. Neural activation in specific brain regions, during trials requiring inhibition of a response, will be compared between groups with certain variants of each genotype. The goals of the proposed study are 1) to test whether variants of dopamine genetic polymorphisms influence brain activation during behavioral inhibition; 2) to test whether variants of dopamine genetic polymorphisms influence the relationship between brain regions underlying behavioral inhibition; and 3) to test whether dopamine genetic polymorphisms interact in influencing brain activation during behavioral inhibition. Results of the proposed project will help to elucidate the genetic and neural basis of the ability to inhibit one's behavior. Dysfunction in inhibitory control is of extreme clinical relevance, as elevated deficits in inhibition, or impulsivity, are seen across a range of mental disorders; however, before this is studied in clinical populations, we must first understand how it works in a healthy population. By combining genetic and neural information in a single study, the results may ultimately influence future ways in which we diagnose, classify, and treat forms of mental illness. [unreadable] [unreadable] [unreadable]